Historically, cell movement has been studied using in vitro or invertebrate systems. This proposal describes the application of the tools of mouse developmental genetics and biochemistry to understanding the regulation of vertebrate cell movement. It focuses on the role of plexin-A1, a semaphorin co-receptor previously implicated in axon guidance. Preliminary evidence suggests that plexin-A1 is required for the regulation of diverse developmental events including ventral folding, heart morphogenesis and angiogenesis. This proposal describes four sets of experiments designed to explore how plexin-A1 directs these morphogenetic processes. First, detailed molecular and cellular analysis of plexin-Al-deficient mouse embryos will clarify the role ofplexin-A1 in ventral folding. Second, chimera analysis will be used to identify which cells use plexin-A1 to direct morphogenesis. Third, analysis of other mutants with similar ventral folding defects will reveal how other molecules interact with plexin-A1 to execute ventral folding. Fourth, a combination of biochemical and developmental genetic approaches will address the mechanism of plexin signaling. By illuminating the role of plexin signaling in development, these studies may provide understanding into congenital disease as well as how cell movement is co-opted by pathologic processes such as tumor invasion and tumor angiogenesis.